The present invention relates to preferably multi-particulate, oral tramadol preparations, having a controlled active substance release profile which is established in a storage-stable manner by an ethylcellulose coating containing plasticizer even without heat treatment.
Multiparticulate, controlled release tramadol preparations having a controlled release coating of ethylcellulose are known in the prior art. DE-A-196 30 035 accordingly describes multiparticulate tramadol preparations in the form of pellets which are provided with a controlled release coating of ethylcellulose. To this end, accretion pellets are coated with one or more ethylcellulose membrane layers which are applied from solutions in organic solvents. This production method has the disadvantage that the organic solvents must be recovered on environmental grounds, thus rendering this process somewhat costly. It is moreover disadvantageous to use organic solvents in the production of pharmaceuticals.
Where controlled release coatings of aqueous ethylcellulose dispersions are applied onto substrates, it is generally recognized by experts that, once produced, such coatings do not usually provide storage-stable active substance release profiles. Such ethylcellulose coatings are indeed known to have a tendency to xe2x80x9cpost-filmingxe2x80x9d, i.e. active substance release is increasingly delayed over storage. In order to overcome this problem, elaborate heat treatment processes at elevated temperature and optionally defined atmospheric humidity are recommended in the prior art in order to achieve a storage-stable release profile within days rather than after several months"" storage (EP-A-0 548 448, EP-A-0 630 646).
According to the teaching of U.S. Pat. No. 5,645,858, it has also been proposed to provide a multiparticulate tramadol preparation in the form of accretion pellets with two or more controlled release coatings of ethylcellulose and to subject the resultant coated accretion pellets of the active substance to a heat treatment process for one day at elevated temperature in order to achieve a stable release profile.
Known methods for producing controlled release coatings from aqueous ethylcellulose. dispersions thus have the disadvantage that a storage-stable active substance release profile of tramadol or tramadol hydrochloride is achieved only by elaborate heat treatment processes or only by multilayer application in combination with a heat treatment process.
The object of the present invention was accordingly to provide oral tramadol preparations having a controlled release ethylcellulose coating which, despite being applied from an aqueous ethylcellulose, dispersion, has a largely storage-stable active substance release profile immediately after the production thereof, and which may optionally, if desired, be still further increased without affecting storage stability.
This is achieved according to the invention by the process of the invention, in accordance with which a preferably multiparticulate, oral, controlled release tramadol preparation or a preparation of a physiologically compatible salt of tramadol having a storage stable active substance release profile is produced. To this end, the preferably multiparticulate active substance preparation is coated with an aqueous ethylcellulose dispersion which contains at least one physiologically compatible, lipophilic diester of a C6-C40 aliphatic or aromatic dicarboxylic acid and a C1-C8 aliphatic alcohol as plasticizer, and the coating is dried at conventional temperatures.
The controlled release tramadol preparations produced in this manner surprisingly exhibit a storage stable active substance release profile immediately after the production thereof, without any heat treatment subsequent to the conventional drying being necessary. The controlled release tramadol preparations produced according to the invention exhibit a so-called coalesced ethylcellulose coating, in which the discrete ethylcellulose particles have coalesced to form a coating.
The controlled release active substance preparations according to the invention furthermore have the unexpected advantage that the active substance release profile may be increased as desired without the storage stability of the increased active substance release profile being impaired. This is achieved by heat treating the controlled release active substance preparations after production thereof at temperatures of  greater than 35xc2x0 C. until the selected, increased release profile is achieved.
Tramadol or preferably a physiologically compatible salt of tramadol, such as tramadol hydrochloride, is used for the process according to the invention in the form of tablets, microtablets, granules, crystals, pellets, such as extrusion or accretion pellets preferably having a size of 0.3 to 2.5 mm. The production of such multiparticulate substrates is known to persons skilled in the art.
The controlled release coatings are produced by using aqueous ethylcellulose dispersions having a concentration of water-insoluble ethylcellulose of 3 to 35 wt. %, preferably of 10 to 25 wt. %. The aqueous ethylcellulose. dispersions which are used as the coating material contain at least one physiologically compatible lipophilic diester of a C6-C40, preferably C6-C30, particularly preferably C10-C16 aliphatic or aromatic dicarboxylic acid and a C1-C8, preferably C2-C6, particularly preferably C2-C5 aliphatic alcohol as a plasticizer. The plasticizers used are preferably dibutyl phthalate, diethyl phthalate, dibutyl sebacate or diethyl sebacate, particularly preferably dibutyl sebacate. The quantity of plasticizer is from 5 to 50 wt. %, preferably 10 to 40 wt. %, particularly preferably 10 to 30 wt. %, relative to ethylcellulose. Especially preferred controlled release coatings are those prepared from ethylcellulose containing 10 to 30 wt. % dibutyl sebacate, relative to the ethylcellulose.
The aqueous ethylcellulose dispersions used may be commercial products such as, for example, Aquacoat(trademark) or Surelease(trademark). Such dispersions, such as for example Surelease, may already contain the necessary plasticizer. It is, however, also possible to incorporate the plasticizers into the aqueous ethylcellulose dispersion, preferably with the assistance of surfactants or emulsifiers, such as for example polysorbate 80 (Tween 80(trademark)). It is particularly preferred to use an aqueous ethylcellulose dispersion which already contains the plasticizer as a component during the production of the ethylcellulose dispersion, such as the commercial product Surelease E-7-7050(trademark).
The release profiles obtained immediately after production may be adjusted by methods known to persons skilled in the art, such as for example by varying the particular thickness of the coating or by addition of further auxiliary substances as coating constituents. Pigments, such as iron oxides, titanium dioxide, lubricants, such as talcum, Aerosil, glycerol monostearate, hydrophilic pore-formers such as lactose, polyethylene glycol, mannitol and/or water-soluble polymers, such as hydroxypropylmethylcellulose, polyvidone, may be considered for this purpose. It is also possible by blending with other coating dispersions, such as for example Eudragit(trademark) RS 30D, RL 30D, NE 30D, or dispersions of film-formers resistant to gastric juices, such as for example Endragit L 30D, to control the release of the active substance such that a delay on the order of at least 4 hours up to 24 hours is achieved.
The controlled release coating of ethylcellulose is produced by coating the active substance substrates, once produced, with the aqueous dispersion by spraying, preferably using the fluidized bed process, and simultaneously drying at conventional temperatures. Desired product temperatures in this process are at least 35xc2x0 C., preferably 35xc2x0 C. to 80xc2x0 C., particularly preferably 40xc2x0 C. to 45xc2x0 C., which are established using feed air at a temperature of at least 50xc2x0 C., preferably of 55xc2x0 C. to 70xc2x0 C.
In the event that the storage stable release profile of the active substance obtained immediately after production is subsequently to be changed, it is possible after drying to expose the controlled release active substance preparations to heat treatment at temperatures of  greater than 35xc2x0 C. until the desired increase in release of the active substance is achieved. By measuring the particular active substance release profile as a function of the duration of the heat treatment process at a specific temperature, persons skilled in the art are able to determine the correlation between release profile and heat treatment conditions by means of simple tests. It is thus straightforwardly possible to establish an appropriate active substance release profile at any time.
The present invention accordingly also provides oral, preferably multiparticulate, controlled release preparations of tramadol or a physiologically compatible salt of tramadol having a storage stable active substance release profile. The controlled release tramadol or tramadol salt preparations according to the invention are characterized by the active substance preparation being provided with a coalesced ethylcellulose coating, which has been obtained by coating the preferably multiparticulate active substance preparation with an aqueous ethylcellulose dispersion containing a plasticizer which is comprised of a lipophilic diester of a C6-C40 aliphatic or aromatic dicarboxylic acid and a C1-C8 aliphatic alcohol, and which provides a storage stable active substance release profile after only drying the coating at conventional temperature. The active substance release profile may be increased by subsequent heat treatment at temperatures of  greater than 35xc2x0 C. without affecting storage stability.
In order to protect the very readily water-soluble tramadol or tramadol salt, such as tramadol hydrochloride, during coating with the aqueous ethylcellulose dispersion, it may be advantageous to apply a protective coating to the active substance substrate before application of the controlled release coating. The protective coating is preferably applied for isolation purposes in a quantity of 1 to 10 wt. %, preferably of 2.5 to 5 wt. %, relative to the quantity of the active substance substrate to be coated. This results in no substantial reduction in the application rate required for controlled release purposes, but avoids dissolution of the water-soluble active substance during coating with ethylcellulose and prevents the active substance from penetrating the controlled release film.
Aqueous solutions of water-soluble polymers, such as for example hydroxypropylmethylcellulose or hydroxypropylcellulose, poylvidone with or without further auxiliary substances, such as for example talcum, or lipophilic substances applied by melt coating or from organic solutions, such as for example fatty alcohols, fatty acids, fats, waxes, glycerol monostearate, glycerol behenate types may be used as a protective coating material.
External coatings over the controlled release substrates are generally applied in order to prevent adhesion of the substrates during storage. The external coatings may, however, also be functional coatings which provide additional protection, for example against elevated atmospheric humidity or against the penetration of gastric acid into the substrate. The quantity of the external coating is determined in accordance with its function and ranges from xe2x89xa61 wt. % to provide protection against sticking up to 30 wt. % to increase resistance to gastric juices.